Summary for UKPID OPIOID ANALGESIC Kathryn Pughe, BSc (Hons) MRPharmS National Poisons Information Service (Newcastle Centre) Regional Drug & Therapeutics Centre Wolfson Building Claremont Place Newcastle upon Tyne NE1 4LP UK This monograph has been produced by staff of a National Poisons Information Service Centre in the United Kingdom. The work was commissioned and funded by the UK Departments of Health, and was designed as a source of detailed information for use by poisons information centres. Peer review group: Directors of the UK National Poisons Information Service. PRODUCT DETAILS Name Generic Alfentanil hydrochloride Proprietary Rapifen, Rapifen Intensive Care Chemical Group/Family Opioid analgesic BNF 4.7.2 Reference Number CAS 71195-58-9 alfentanil CAS 69049-06-5 alfentanil HCl, anhydrous CAS 70879-28-6 alfentanil HCl, monohydrate Product licence 0242/0091 (Rapifen) 0242/0137 (Rapifen Intensive Care) Manufacturer/Supplier Janssen-Cilag Ltd PO Box 79 Saunderton High Wycombe Bucks HP14 4HJ Tel 01494 567567 Fax 01494 567568 Presentation Rapifen Clear, colourless injection alfentanil HCl 0.5 mg/ml 2 ml and 10 ml ampoules, packs of 10 Rapifen Intensive Care Clear, colourless injection alfentanil HCl 5 mg/ml 1 ml ampoules, packs of 10 Physico-Chemical Properties Chemical structure C21H32N6O3HCl.H2O N-[1-[2-(4-Ethyl-5-oxo-2-tetrazolin-1-yl)ethyl]-4- (methoxymethyl)-4-piperidyl]propionanilide hydrochloride monohydrate Physical state at room temperature White crystalline powder Molecular weight (free base) 471.0 (416.5) pKa (>N-) 6.5 Solubility in alcohol 1 in 5 in water 1 in 7 Name Generic Buprenorphine Proprietary Temgesic Chemical Group / Family Opioid analgesics BNF 4.7.2 Reference Number CAS 52485-79-7 buprenorphine CAS 53152-21-9 buprenorphine HCl Product licence numbers 0063/0007 (0.3 mg inj) 0063/0008 (0.2 mg tabs) 0063/0009 (0.4 mg tabs) Manufacturer/Supplier Reckitt & Colman Products Ltd., Dansom Lane, Hull HU8 7DS Tel: 01482 326151 Fax: 01482 582526 Presentation Temgesic Sublingual White 200 mcg tabs marked with a 2 and a sword symbol in blister pack of 5x10 White 400 mcg tabs marked with a 4 and a sword symbol in blister pack of 5x10 Temgesic Injection Colourless injection 300 mcg/ml, 1 ml ampoules, packs of 5 Physico-Chemical Properties Chemical structure C29H41NO4.HCl N-Cyclopropylmethyl-7-[1-(S)-hydroxy-1,2,2-trimethylpropyl]- endoethano-6,7,8,14-tetrahydro-nororipavine Physical state at room temperature white odourless powder Molecular weight (free base) 468 pKa 8.42, 9.92 Solubility in alcohol 1 in 24 Name Generic Codeine phosphate Compound prep - Co-codamol, Co-codaprin Proprietary Compound preparations - Aspav, Codafen Continus, Galcodine, Kaodene, Kapake, Migraleve, Panadeine, Paracodol, Parake, Solpadol, Terpoin, Tylex Also in various OTC products Synonym / street Schoolboy Chemical Group/Family Opioid analgesics BNF 4.7.2 Reference Number CAS 52-28-8 (Codeine PO4 - anhydrous) CAS 41444-62-6 (Codeine PO4 - hemihydrate) CAS 5913-76-8 (Codeine PO4 - sesquihydrate) Manufacturer/Supplier Generic Presentation 15 mg round white tabs in containers of 100 30 mg round white tabs in containers of 100 or 500 60 mg round white tabs in containers of 100 25 mg/5 ml syrup bottles of 100 ml and 500 ml 60 mg/ml inj in boxes of 10 amps 15 mg/5 ml linctus bottles of 100 ml and 1L 3 mg/5 ml paediatric linctus bottles of 100 ml and 1L Physico-Chemical Properties Chemical structure C18H21NO3.H3PO4.´H2O 7,8-Didehydro-4,5alpha-epoxy-3-methoxy-N-methylmorphinan- 6alpha-ol phosphate hemihydrate Physical state at room temperature fine, white, needle-shaped crystals or a white crystalline powder Molecular weight (free base) 299.4 pKa 8.2 Solubility in alcohol 1 in 325 in water 1 in 4 Name Generic Dextromoramide tartrate Proprietary Palfium Synonym / street Peach palf Chemical Group / Family Opioid analgesics BNF 4.7.2 Reference Number CAS 2922-44-3 Product licence numbers 0075/5015R (5 mg tabs) 0075/0035R (10 mg tabs) 0075/5014R (10 mg suppositories) Manufacturer/Supplier Boehringer Mannheim UK (Pharmaceuticals) Ltd, Simpson Parkway, Kirkton Campus, Livingston, West Lothian EH54 7BH Tel 01506 412512 Fax 01506 411395 Presentation Palfium White scored 5 mg tabs in blister packs of 60 Peach scored 10 mg tabs in blister packs of 60 Light cream 10 mg suppositories in packs of 10 Physico-Chemical Properties Chemical structure C25H32N2O2.C4H6O6 (d)-1-(3-Methyl-4-morpholino-2,2-diphenylbutyryl)- pyrrolidine tartrate Physical state at room temperature white, amorphous or crystalline powder Molecular weight (free base) 542.6 (392.5) pKa 7.1 Solubility in alcohol 1 in 85 in water 1 in 25 Name Generic Dextropropoxyphene hydrochloride Proprietary Doloxene Compound preparations - Cosalgesic, Distalgesic, Doloxene Compound Chemical Group / Family Opioid analgesics BNF 4.7.2 Reference Number CAS 1639-60-7 Product licence number 0006/5068 Manufacturer/Supplier Eli Lilly & Co Ltd Dextra Court, Chapel Hill, Basingstoke, Hampshire, RG21 5SY Tel 01256 315000 Fax 01256 315569 Compound preparations available from APS, Berk, Cox, Dista, Norton, Sterwin Presentation Doloxene Opaque pink 65 mg caps marked Lilly H64 in blister packs of 10 x 10 Doloxene compound Light grey opaque cap, red opaque body marked H91 in blister packs of 100 Physico-Chemical Properties Chemical structure C22H29NO2.HCl (d)-(1S,2R)-1-Benzyl-3-dimethylamino-2-methyl-1-phenylpropyl proprionate hydrochloride Physical state at room temperature white to slightly yellow odourless powder Molecular weight (free base) 375.9 (339.5) pKa (amino) 6.3 Solubility in alcohol 1 in 1.5 in water 1 in 0.3 Name Generic Diamorphine hydrochloride Proprietary Diagesil Synonym / street Heroin; Boy; Brown sugar; Black tar; Chinese; Chinese rock; Crap; Dana; Dujie; Elephant; H;Harry; Horse; Joy powder; Junk; Mexican brown;Noise; Persia; Poor man's speedball; Rock; Rock'n roll; Rufus; Smack; Speedball; Stuff; TNT; White elephant; White junk; White stuff. Chemical Group / Family Opioid analgesics BNF 4.7.2 Reference Number CAS 561-27-3 (diamorphine) CAS 1502-96-0 (diamorphine HCl) Product licence numbers 5 mg inj 0039/5662 10 mg inj 0039/5663 30 mg inj 0039/5665 100 mg inj 0039/0154 500 mg inj 0039/0163 Manufacturer/Supplier Generics - Aurum, Berk, CP, Evans, Hillcross Evans Medical Ltd Evans House Regent Park Kingston Rd Leatherhead Surrey KT22 7PQ Tel 01372 364000 Fax 01372 364190 Presentation Round white scored 10 mg tabs in packs of 100 (Aurum) White / off-white powder for reconstitution, 5 mg, 10 mg, 30 mg, 100 mg and 500 mg injections in boxes of 5 ampoules Physico-Chemical Properties Chemical structure C21H23NO5.HCl.H2O 7,8-Dehydro-4,5-epoxy-N-methyl morphinan-3,6-diol diacetate hydrochloride Physical state at room temperature almost white crystalline powder Molecular weight (free base) 423.9 (369.4) pKa 7.6 Solubility in alcohol 1 in 12 in water 1 in 1.6 Name Generic Dihydrocodeine tartrate Proprietary DF 118, DF 118 Forte, DHC Continus Compound preparations - Co-dydramol, Galake, Paramol, Remedeine, Remedeine Forte Chemical Group / Family Opioid analgesics BNF 4.7.2 Reference Number CAS 125-28-0 (dihydrocodeine) CAS 5965-13-9 (dihydrocodeine tartrate) Product licence numbers 0337/0230 (DF118 Forte) 0337/0196 (DF118 Inj) 0337/0115 (60 mg tabs) 0337/0140 (90 mg tabs) 0337/0141 (120 mg tabs) 0337/0197 (elixir) 0530/0229 (30 mg tabs by Norton) Manufacturer/Supplier Napp, Aurum and generics Napp Laboratories Ltd Cambridge Science Park Milton Road Cambridge CB4 4GW Tel 01223 424444 Fax 01223 424441 Presentation Generics 30 mg tabs bottles of 20, 100, 500 Dihydrocodeine Elixir BP Brown syrup of 10 mg/5ml in bottles of 150 ml and 1 litre DF118 Injection Colourless solution of 50 mg/ml in boxes of 5 ampoules DF118 Forte Tablets Round, white 40 mg tabs marked with DF118 and Forte, in bottles of 100 DHC Continus Tablets White capsule-shaped tablets 60 mg tabs m/r, marked DHC 60 packs of 56 90 mg tabs m/r, marked DHC 90 packs of 56 120 mg tab m/r, marked DHC120 pack of 56 Physico-Chemical Properties Chemical structure C18H23NO3.C4H6O6 4,5-Epoxy-3-methoxy-17-methylmorphinan-6-ol tartrate Physical state at room temperature odourless white crystalline powder Molecular weight 451.5 pKa 8.8 Solubility in alcohol sparingly in water 1 in 4.5 Name Generic Dipipanone hydrochloride Proprietary Diconal (with 30 mg cyclizine) Synonym / street Dike Chemical Group / Family Opioid analgesics BNF 4.7.2 Reference Number CAS 467-83-4 (dipipanone) CAS 856-87-1 (dipipanone HCl) Product licence number 0003/5027R Manufacturer/Supplier Glaxo Wellcome Stockley Park West Uxbridge Middlesex UB11 1BT Tel 0800 413524 Fax 0181 990 4372 Presentation Round pink 10 mg tabs, scored and marked WELLCOME F3A, in blister packs of 50 Physico-Chemical Properties Chemical structure C24H31NO.HCl.H20 4,4-Diphenyl-6-piperidino-3-hepanone hydrochloride Physical state at room temperature white crystalline powder Molecular weight (free base) 404.0 (349.5) pKa (amine) 8.5 Solubility in alcohol 1 in 1.5 in water 1 in 40 Name Generic Fentanyl citrate Proprietary Durogesic, Sublimaze Synonym / street China white Chemical Group / Family Opioid analgesics BNF 4.7.2 Reference Number CAS Product licence numbers 0242/0192 (Durogesic 25) 0242/0193 (Durogesic 50) 0242/0194 (Durogesic 75) 0242/0195 (Durogesic 100) 0242/5001R (Sublimaze) Manufacturer/Supplier Janssen-Cilag Ltd Saunderton High Wycombe Buckinghamshire HP14 4HJ Tel 01494 567444 Fax 01494 567445 Presentation Durogesic patches Transparent self-adhesive patches containing a reservoir of fentanyl. '25' patch, marked Durogesic 25 µg fentanyl/h in pink, in boxes of 5 '50' patch, marked Durogesic 50 µg fentanyl/h in green, in boxes of 5 '75' patch, marked Durogesic 75 µg fentanyl/h in blue, in boxes of 5 '100' patch, marked Durogesic 100 µg fentanyl/h in grey, in boxes of 5 Sublimaze injection Clear, colourless, aqueous injection 0.05 mg/ml 2 ml ampoules in packs of 10 0.05 mg/ml 10 ml ampoules in packs of 10 Physico-Chemical Properties Chemical structure C22H28N2O.C6H8O7 N-(1-Phenethyl-4-piperidyl)propionanilide dihydrogen citrate Physical state at room temperature white crystalline powder Molecular weight (free base) 528.6 (336.5) pKa (amino) 8.43 Solubility in alcohol 1 in 140 in water 1 in 40 Name Generic Meptazinol hydrochloride Proprietary Meptid Chemical Group / Family Opioid analgesics BNF 4.7.2 Reference Number CAS 54340-58-8 (meptazinol) CAS 59263-76-2 (meptazinol HCl) CAS 34154-59-1 (+/_ - meptazinol HCl) Product licence number 10536/0007 (tablets) 10536/0008 (injection) Manufacturer/Supplier Monmouth Pharmaceuticals Ltd 3 & 4 Huxley Road Surrey Research Park Guildford Surrey GU2 5RE Tel 01483 565299 Fax 01483 563658 Presentation Oval, orange film-coated 200 mg tabs, marked MPL 023, in 5 blister packs of 20 Clear solution of 100 mg/ml for injection in 1 ml clear glass ampoules in packs of 10 Physico-Chemical Properties Chemical structure C15H23NO.HCl 3-(3-Ethyl-1-methyl-hexahydro-1H-azepin-3-yl)-phenol hydrochloride Physical state at room temperature white or creamy powder Molecular weight (free base) 269.8 (233.3) pKa (phenol) 8.7 (amino) 11.9 Solubility in alcohol - in water - Name Generic Methadone hydrochloride Proprietary Physeptone Synonym / street Doll, dollies, dolophine Chemical Group / Family Opioid analgesics BNF 4.7.2 Reference Number CAS 76-99-3 (methadone) CAS 297-88-1 (methadone, +/_) CAS 1095-90-5 (methadone HCl) CAS 125-56-4 (methadone HCl, +/_) Manufacturer/Supplier Generics- CP, Martindale Glaxo Wellcome Stockley Park West Uxbridge Middlesex UB11 1 BT Tel 0800 413524 Fax 0181 990 4372 Presentation Physeptone Round, white 5 mg tabs, scored and marked WELLCOME L4A in 5 blister strips of 10 10 mg/ml inj in 1 ml ampoules in boxes of 5 and 100 Generics Injections - 10 mg/ml in 1ml, 2 ml, 3.5 ml and 5 ml amps in boxes of 10 Linctus BP in bottles of 500 ml Mixture 1 mg/ml in bottles of 30 ml, 50 ml, 100 ml and 500 ml (also sugar free versions) Physico-Chemical Properties Chemical structure C21H27NO.HCl 6-Dimethylamino-4,4-diphenyl-3-heptanone hydrochloride Physical state at room temperature white or colourless crystalline powder Molecular weight (free base) 345.9 (309.5) pKa (amino) 8.3 Solubility in alcohol 1 in 7 in water 1 in 12 Name Generic Morphine Combination products: Kaolin & Morphine mixture, Morphine & Atropine injection Proprietary Cyclimorph, Morcap SR, MST, MXL, Oramorph, Oramorph SR , Sevredol Synonym / street Cube juice, dreamer, hard stuff, hocus, M, monkey, Miss Emma, morf, morpho Chemical Group / Family Opioid analgesics BNF 4.7.2 Reference Number CAS 57-27-2 (anhydrous morphine) CAS 6009-81-0 (morphine monohydrate) CAS 52-26-6 (anhydrous morphine HCl) CAS 6055-06-7 (morphine HCl trihydrate) CAS 64-31-3 (anhydrous morphine SO4) CAS 6211-15-0 (morphine SO4 hydrate) CAS 302--31-8 (anhydrous morphine tartrate) CAS 6032-59-3 (morphine tartrate trihydrate) Product licence numbers 0003/5022R (Cyclimorph 10) 0003/5023R (Cyclimorph 15) Morcap SR 20 mg 4515/0080 50 mg 4515/0081 100 mg 4515/0082 MST Continus tablets 10 mg 0337/0055; 15 mg 0337/0180; 30 mg 0337/0059; 60 mg 0337/0087; 100 mg 0337/0088; 2000 mg 0337/0149. MST Continus suspensions 20 mg 0337/0165; 30 mg 0337/0166; 60 mg 0337/0225; 100 mg 0337/0226; 200 mg 0337/0227. MXL capsules 0337/0259-0264 (marketing authorisation) Oramorph SR tablets 10 mg 0015/0208; 30 mg 0015/0209; 60 mg 0015/0210; 100 mg 0015/0211 Oramorph solutions 10 mg/5 ml 0015/0122; 20 mg/ml 0015/0125; 10 mg/5 ml UDV 0015/0157; 30 mg/5 ml UDV 0015/0158; 100 mg/5 ml UDV 0015/0159 Sevredol tablets 10 mg 0337/0142; 20 mg 0337/0143; 50 mg 0337/0265 (marketing authorisation) Manufacturer/Supplier Boehringer Ingelheim, Napp, IMS, Sanofi Winthrop, Wellcome. Generics - Evans, Martindale Napp Laboratories Ltd Cambridge Science Park Milton Road Cambridge CB4 4GW Tel: 01223 424444 Fax: 01223 424441 Presentation Cyclimorph inj - 1 ml amps in boxes of 5 Morcap SR - transparent caps containing creamy-white / tan pellets in blister strips of 30 or 60. MST Continus tablets - blister packs of 60 10 mg tabs golden brown; 15 mg tabs green; 30 mg tabs dark purple; 60 mg tabs orange; 100 mg tabs grey; 200 mg tabs teal green. MST Continus susp - cartons of 30 foil sachets containing pink granules. MXL caps - containers of 28 or 30 caps or blister strips of 28 or 30. 30 mg light blue marked MS OD30; 60 mg brown marked MS OD60; 90 mg pink marked MS OD90; 120 mg olive marked MS OD120; 150 mg blue MS OD150; 200 mg rust MS OD200. Oramorph SR tabs - blister pack of 10 or 60. 10 mg greyish orange; 30 mg purple; 60 mg orange; 100 mg grey. Oramorph oral solution - clear, colourless solution 10 mg/5 ml in bottles of 100 ml, 300 ml and 500 ml. Oramorph concentrate - clear, red solution in bottles of 30 ml and 120 ml with calibrated dropper. Oramorph unit dose vials - clear, colourless solution in 5 ml polyethylene vials, packs of 25 vials. Available as 10 mg/5 ml, 30 mg/5 ml and 100 mg/5 ml. Sevredol - film coated, capsule shaped tablets in blister packs and containers of 56 and 112. 10 mg blue marked IR 10; 20 mg pink marked IR 20; 50 mg pale green marked IR 50. Physico-Chemical Properties Chemical structure C17H17NO3.H2O 7,8-Didehydro-4,5-epoxy-3,6-dihydroxy-n-methylmorphinan Physical state at room temperature colourless white crystalline powder Molecular weight (anhydrous) 303.4 (285.3) pKa tertiary amine 7.93 phenolic hydrogen 9.63 Solubility in alcohol 1 in 250 in water 1 in 5000 Name Generic Nalbuphine hydrochloride Proprietary Nubain Chemical Group / Family Opioid analgesics BNF 4.7.2 Reference Number CAS 20594-83-6 (nalbuphine) CAS 23277-43-2 (nalbuphine HCl) Product licence number 11173/0013 Manufacturer/Supplier Du Pont Pharmaceuticals Ltd Avenue One Letchworth Garden City Herts SG6 2HU Tel 01462 488200 Fax 01462 488319 Presentation Clear, colourless solution of 10 mg/ml in 1 ml and 2 ml ampoules in boxes of 10 Physico-Chemical Properties Chemical structure C21H27NO4.HCl (I)-(-)-(5R,6S,14S)-9a-(Cyclobutylmethyl)-4,5-epoxymorphinan- 3,6alpha,14-triol hydrochloride Physical state at room temperature white to off-white powder Molecular weight (free base) 393.9 (357.4) pKa 8.71, 9.96 Solubility in alcohol soluble in water soluble Name Generic Oxycodone Proprietary - Chemical Group/Family Opioid analgesics BNF 4.7.2 Reference Number CAS 76-42-6 (oxycodone) CAS 124-90-3 (oxycodone HCl) Manufacturer/Supplier BCM Specials Presentation Only available in UK through above supplier as suppositories for use in palliative care Physico-Chemical Properties Chemical structure C18H21NO4,HCl Physical state at room temperature NIF Molecular weight (free base) 351.8 pKa NIF Solubility in alcohol NIF in water NIF Name Generic Papaveretum Proprietary Aspav (with aspirin) Chemical Group / Family Opioid analgesics BNF 4.7.2 Reference Number CAS -NA Product licence 0142/5597 (Aspav) Manufacturer/Supplier Martindale Pharmaceuticals Bampton road Harold Hill Romford Essex RM3 8UG Tel: 01708 386660 Fax: 01708 384032 Presentation Papaveretum inj 7.7 mg/ml - 1 ml amps in boxes of 10 15.4 mg/ml - 1 ml amps in boxes of 10 Papaveretum with hyoscine inj 15.4 mg/ml + hyoscine 400 mcg/ml - 1 ml amp in boxes of 10 Aspav Round, white tablets containing 7.71 mg papaveretum + 500 mg aspirin, marked AP, in containers of 100 Physico-Chemical Properties Chemical structure mixture of opium alkaloid hydrochlorides 253 parts of morphine HCl 23 parts of papaverine HCl 20 parts of codeine HCl Physical state at room temperature yellowish-brown powder Molecular weight (free base) NA pKa NA Solubility in alcohol NA in water NA Name Generic Pentazocine hydrochloride Proprietary Fortral Fortagesic ( with paracetamol) Chemical Group / Family Opioid analgesics BNF 4.7.2 Reference Number CAS 359-83-1 (pentazocine) CAS 2276-52-0 (pentazocine HCl) CAS 64024-15-3 (pentazocine HCl) Product licence numbers 11723/0028 (Fortagesic) 11723/0033 (Fortral 25 mg tabs) 11723/0090 (Pentazocine 25 mg tabs) 11723/0088 (Pentazocine 50 mg caps) 11723/0031 (Fortral injection) 11723/0032 (Fortral suppositories) Manufacturer/Supplier Sanofi Winthrop Ltd (& Sterwin) One Onslow Street Guildford Surrey GU1 4YS Tel 01483 505515 Fax 01483 35432 Presentation Pentazocine Orange / grey 50 mg caps, marked PZN 50; Cox NP; PT50 G; yellow / grey ftl 50 in bottles of 100 Round, white 25 mg tabs, marked PZN 25; Cox PZ; S 24; G PT 25 in bottles of 100 Fortral Round, white 25 mg tabs, marked STERWIN / Fortral in bottles of 100 30 mg/ml inj 1 ml and 2 ml amps in boxes of 10 50 mg supp in boxes of 20 Fortagesic Round, white 15 mg tabs, marked FORTAGESIC in bottles of 100 Physico-Chemical Properties Chemical structure C19H27NO.HCl 1,2,3,4,5,6-Hexahydro-6,11-dimethyl-3-(3-methylbut-2-enyl)-2,6- methano-3-benzazocin-gamma-ol hydrochloride Physical state at room temperature white or cream crystalline powder Molecular weight (free base) 321.9 (285.4) pKa 8.7, 10.0 Solubility in alcohol 1 in 16 in water 1 in 30 Name Generic Pethidine hydrochloride Proprietary Pamergan P100 (with promethazine) Synonym / street Meperidine Chemical Group / Family Opioid analgesics BNF 4.7.2 Reference Number CAS 57-42-1 (pethidine) CAS 50-13-5 (pethidine HCl) Product licence numbers Marketing authorisation number 0156/0020R (Pamergan P100) Manufacturer/Supplier Generics - Martindale, Roche Martindale Pharmaceuticals Brampton Road Harold Hill Romford Essex RM3 8UG Tel 01708 386660 Fax 01708 384032 Presentation 50 mg tabs in containers of 50 50 mg/ml inj in boxes of 10 100 mg/ml inj in boxes of 10 Pamergan P100 50 mg inj with promethazine 25 mg/ml - 2 ml ampoules in packs of 10 Physico-Chemical Properties Chemical structure C15H21NO2.HCl Ethyl 1-methyl-4-phenylpiperine-4-carboxylate hydrochloride Physical state at room temperature white colourless crystalline powder Molecular weight (free base) 283.8 (247.3) pKa 8.6 Solubility in alcohol 1 in 20 in water >1 in 2 Name Generic Phenazocine hydrobromide Proprietary Narphen Chemical Group / Family Opioid analgesics BNF 4.7.2 Reference Number CAS 127-35-5 (phenazocine) CAS 1239-04-9 (phenazocine HBr) Product licence number 0337/0198 Manufacturer/Supplier Napp Laboratories Ltd Cambridge Science Park Milton Road Cambridge CB4 4GW Tel 01223 424444 Fax 01223 424441 Presentation Round white 5 mg tabs, marked N / 5 in containers of 100 Physico-Chemical Properties Chemical structure C22H27NOHBr.´H2O 1,2,3,4,5,6-Hexahydro-6,11-dimethyl-3-phenethyl-2,6-methaon-3- benzazocin-8-ol hydrobromide hemihydrate Physical state at room temperature white microcystalline powder Molecular weight (free base) 411.4 (321.4) pKa (amino) 8.5 Solubility in alcohol 1 in 45 in water 1 in 350 Name Generic Phenoperidine Proprietary Operidine Chemical Group/Family Opioid analgesics BNF 4.7.2 Reference Number CAS 562-26-5 (phenoperidine) CAS 3627-49-4 (phenoperidine HCl) Product licence number 0242/5000R Manufacturer/Supplier Janssen-Cilag Ltd Saunderton High Wycombe Buckinghamshire HP14 4HJ Tel: 01494 567444 Fax: 01494 567445 Presentation Clear, colourless solution containing 1 mg/ml for inj in 2 ml amps in packs of 10 and 10 ml amps in packs of 5 Physico-Chemical Properties Chemical structure C23H29NO3.HCl Ethyl 1-(3-hydroxy-3-phenylpropyl)-4-phenylpiperidine-4- carboxylate hydrochloride Physical state at room temperature white, crystalline powder Molecular weight (free base) 403.9 (367.5) pKa 8.01 Solubility in alcohol 1 in 10 in water - Name Generic Pholcodine Proprietary Galenphol, Pavacol-D Also in various OTC preps Chemical Group/Family Opioid analgesics BNF 4.7.2 Reference Number CAS 509-67-1 (anhydrous pholcodine) Manufacturer/Supplier Generics - APS, Norton Galen Ltd Seagoe Industrial Estate Craigavon Northern Ireland BT63 5UA Tel 01762 334974 Presentation Pholcodine linctus 5 mg/5 ml in bottles of 100 ml, 140 ml, 200 ml, 300 ml, 2 L Pholcodine linctus strong 10 mg/5 ml in bottles of 100 ml, 2 L Pholcodine paediatric linctus 2 mg/5 ml in bottles of 90 ml, 2 L Physico-Chemical Properties Chemical structure C23H30N2O4.H2O 3-O-(2-Morphinoethyl)morphine monohydrate Physical state at room temperature colourless crystalline powder Molecular weight (anhydrous) 416.5 (398.5) pKa 8.0, 9.3 Solubility in alcohol 1 in 3 in water 1 in 50 Name Generic Tramadol hydrochloride Proprietary Tramake, Zydol, Zydol SR Chemical Group/Family Opioid analgesics BNF 4.7.2 Reference Number CAS 27203-92-5 (tramadol) CAS 22204-88-2 (tramadol HCl) CAS 36282-47-0 (tramadol HCl) Product licence numbers 08821/0005 (Zydol caps) 08821/0004 (Zydol amps) Manufacturer/Supplier Searle PO Box 53 Lane End Road High Wycombe Buckinghamshire HP12 4HL Tel: 01494 521124 Fax: 01494 447872 Presentation Zydol Green / yellow 50 mg caps - blister packs of 10, 100 and 140 50 mg soluble tabs in packs of 20 and 100 Colourless aqueous solution containing 100 mg in 2 ml amps in boxes of 5 Zydol SR Round white 100 mg tabs, marked T1 in blister packs of 60 and 100 Round orange 150 mg tabs, marked T2 in blister packs of 60 Round orange 200 mg tabs, marked T3 in blister packs of 60 Tramake Yellow / green 50 mg caps, marked TRAMAKE, in blister packs of 100 Physico-Chemical Properties Chemical structure C16H25NO2,HCl (+/-) - trans-2- Dimethyl-nomethyl-methoxyphenyl)cyclohexanol hydrochloride Physical state at room temperature NIF Molecular weight (free base) 299.8 pKa NIF Solubility in alcohol NIF in water NIF SUMMARY The effects in overdosage will be potentiated by simultaneous ingestion of alcohol and other psychotropic drugs. Progressive depression of the central nervous system leading to deep coma, cyanosis and marked reduction of the respiratory rate before respiratory arrest occurs. The pupils are usually pin-point in size and nausea and vomiting are common in less severe cases. Hypotension, tachycardia, hallucinations and rhabdomyolysis have been reported. Additional features in addicts: Overdosage in these cases may be due to ingestion, smoking (e.g. heroin) or intravenous or subcutaneous injection. Injection sites may therefore be present in some cases, particularly over the antecubital fossae, feet and groins. Beware of the risks of hepatitis B and HIV infection. Non-cardiogenic pulmonary oedema and rhabdomyolisis are particularly common after intravenous injection of opioid analgesics. Management 1. Give naloxone (NARCAN) preferably intravenously if coma or respiratory depression are present. Adults: naloxone 800 mcg IV to start, then 400 mcg every 2 minutes until the patient improves (respiratory rate, consciousness, pupil size) or until 3.2 mg have been given. Children: 0.01 mg/kg body weight, increase up to 0.1 mg/kg if no response or sub-optimal response; Neonates: Initial doses of 10 to 30 mcg/kg IV. Failure of a definite opioid overdose to respond to naloxone suggests that another CNS depressant drug or brain damage is present. 2. Observe the patient carefully for recurrence of CNS and respiratory depression. The plasma half-life of naloxone is shorter than that of most opioid analgesics. Repeated doses of naloxone may be required. Intravenous infusions of naloxone have been recommended in situations where repeated doses have been necessary. Set up an infusion (5 x 400 mcg ampoules naloxone = 2 mg in 500 ml 5% dextrose) at a rate equal to 2/3 of the dose required to wake the patient per hour. Infusions are not substitutes for frequent review of the patients clinical state and administration of bolus doses of naloxone as required. 3. Do not delay in establishing a clear airway, adequate ventilation and oxygenation if there is no response to naloxone. 4. Assisted ventilation with positive end-expiratory pressure may be necessary if pulmonary oedema is a complication. 5. Other supportive measures as indicated by the patient's progress. SUBSTANCE SUBSTANCE /PRODUCT NAME Alfentanil Buprenorphine Codeine Dextromoramide Dextropopoxyphene Diamorphine Dihydrocodeine Dipipanone Fentanyl Meptazinol Methadone Nalbuphine Opium Oxycodone Pentazocine Pethidine Phenazocine Phenoperidine Pholcodine Tramadol PROPERTIES USES Indications Opioid analgesics are mainly used for the relief of moderate to severe pain. They are also used in anaesthesia for premedication induction or maintenance. Morphine is generally the standard against which other opioids are compared and is considered by many to be the analgesic of choice for severe pain associated with terminal illness. Opioids with a quicker onset and shorter duration of action such as fentanyl are preferred for use in anaesthesia. Codeine and pholcodine are used for the suppression of cough; for intractable cough in terminal illness morphine or diamorphine may be used. Methadone is used in the treatment of opioid dependence. Therapeutic doses SUMMARY Opioids are subject to dosage variability based on the intended indication and the patient's ability to handle the drug. The goal of therapy for analgesia is to use the smallest effective dose. The following summarizes usual dosages. ALFENTANIL By iv infusion with assisted ventilation adult and child initially 50 to 100 micrograms per kg over 10 mins or as a bolus followed by maintenance of 0.5 - 1 microgram/kg/min. Analgesia and suppression of respiratory activity during intensive care, with assisted ventilation, initially 2 mg/hour (approx. 30 microgram/kg/hour), adjusted according to response (usual range 0.5-10 mg/hour); more rapid initial control may be obtained with an iv dose of 5 mg in divided portions over 10 minutes (slowing if hypotension or bradycardia occur); additional doses of 0.5-1 mg may be given by iv injection during short painful procedures. By iv injection, spontaneous respiration, adult, initially up to 500 micrograms over 30 seconds; supplemental 250 micrograms. With assisted ventilation adult and child initially 30-50 micrograms/kg; supplemental 15 micrograms/kg BUPRENORPHINE Pain - by im or slow iv injection 300-600 micrograms every 6-8 hours; child over 6 months 3-6 microgram/kg every 6-8 hours (max 9 microgram/kg). By sublingual administration, initially 200-400 microgram every 8 hours, increasing if necessary to 200-400 micrograms every 6-8 hours; child over 6 months, 16-25 kg, 100 micrograms; 25-37.5 kg, 100-200 micrograms; 37.5-50 kg, 200-300 micrograms. Premedication - by sublingual administration 400 micrograms, by im injection 300 micrograms Peri-operative analgesia - by slow iv injection, 300-450 micrograms CODEINE Mild to moderate pain - 30 to 60 mg orally, every 4 hours when necessary, to a maximum of 240 mg daily. Child, 1-12 years, 3 mg/kg daily in divided doses By intramuscular injection 30-60 mg every 4 hours when necessary Diarrhoea - 30 mg 3-4 times daily (range 15-60 mg). Child not recommended. Cough - 5-10 ml 3-4 times daily; child 5-12 years, 2.5-5 ml 3-4 times daily. Paediatric linctus, child 1-5 years 5 ml 3-4 times daily. DEXTROMORAMIDE Oral 5 mg increasing to 20 mg when required. Rectal 10 mg when required. Child not recommended. DEXTROPOPOXYPHENE 65 mg every 6-8 hours when necessary 65 mg dextropopoxyphene hydrochloride = 100 mg dextropopoxyphene napsylate Child not recommended DIAMORPHINE Acute pain by sc or im injection 5 mg repeated every 4 hrs if necessary (up to 10 mg for heavier well-muscled patients). By slow iv injection quarter to half corresponding im dose. Myocardial infarction, by slow iv injection (1 mg/minute), 5 mg followed by a further 2.5-5 mg if necessary; elderly or frail patients, reduce dose by half. Acute pulmonary oedema, by slow iv injection (1 mg/minute), 2.5-5 mg. Chronic pain, oral, sc or im injection 5-10 mg regularly every 4 hrs; increased according to needs. Child not recommended. DIHYDROCODEINE Oral 30 mg every 4-6 hrs when necessary. Child over 4 yrs 0.5-1 mg/kg every 4-6 hrs Deep sc or im injection up to 50 mg every 4-6 hrs if necessary. Child over 4 yrs 0.5-1 mg/kg every 4-6 hrs DIPIPANONE Diconal (dipipanone 10mg, cyclizine 30 mg) 1 tablet gradually increased to 3 tablets every 6 hours. Child not recommended. FENTANYL By iv injection, spontaneous respiration 50-200 micrograms, then 50 micrograms as required; Child, 3-5 micrograms/kg then 1 microgram/kg as required. With assisted ventilation 0.3-3.5 mg, then 100-200 micrograms as required; Child, 15 micrograms/kg then 1-3 micrograms/kg as required. Patches - apply to skin on torso or upper arm and replace after 72 hours. Child not recommended. MEPTAZINOL Oral 200 mg every 3-6 hrs as required. Child not recommended. By im injection 75-100 mg every 2-4 hrs if necessary, obstetric analgesia 100-150 mg according to patient's weight (2 mg/kg). Child not recommended. By slow iv injection 50-100mg every 2-4 hrs if necessary. Child not recommended. METHADONE Pain - oral, sc or im injection 5-10 mg every 6-8 hrs, adjusted according to response. Child not recommended. Opioid dependence - initially 10-20 mg daily, increased by 10-20 mg daily until no signs of withdrawal or intoxication; usual dose 40-60 mg daily. Child not recommended. Cough in terminal disease - linctus, 2.5-5 ml every 4-6 hours, reduced to twice daily on prolonged use. MORPHINE Acute pain - by sc or im injection 10 mg every 4 hrs if necessary (15 mg for heavier well-muscled patients); Child, up to 1 month 150 micrograms/kg, 1-12 months 200 micrograms/kg, 1-5 years 2.5-5 mg/kg, 6-12 years 5-10 mg. By slow iv injection quarter to half corresponding im dose. Chronic pain - oral, sc or im injection 5-20 mg regularly every 4 hrs; increased according to needs. Rectal, 15-30 mg regularly every 4 hours. (NB. modified release preparations have different dosage schedules). Myocardial infarction, by slow iv injection (2 mg/minute), 10 mg followed by a further 5-10 mg if necessary. Elderly or frail patients reduce dose by half. Acute pulmonary oedema, by slow iv injection (2 mg/minute) 5-10 mg. Analgesia - by sc or im injection, up to 10 mg 1-1´ hours before operation; child, by im injection, 150 microgram/kg. NALBUPHINE Pain - by sc, im, or iv injection, 10-20 mg for 70 kg patient every 3-6 hrs, adjusted according to response; Child up to 300 micrograms/kg repeated once or twice as necessary. Myocardial infarction - by slow iv injection, 10-20 mg repeated after 30 minutes if necessary. Premedication - by sc, im or iv injection, 100-200 micrograms/kg. Induction - by iv injection, 0.3-1 mg/kg over 10-15 minutes. Intra-operative analgesia, by iv injection, 250-500 micrograms/kg at 30 minute intervals. OPIUM Parenteral: 5-20 mg by im or sc injection every 4-5 hours as needed Rectal: 1 suppository once or twice a day OXYCODONE Analgesia: 5 mg every 6 hours as needed, or 4.88 mg of the combined salt every 6 hours as needed. Children 6-12 years 0.61 mg of the combined salt every 6 hours as needed. Children 12 years or older 1.22 mg of the combined salt every 6 hours as needed. OXYMORPHONE Parenteral Analgesia - initially 1-1.5 mg by sc or im injection every 4-6 hours as needed. Initial iv dose 0.5 mg, increased cautiously until satisfactory analgesia obtained. Labour - 0.5-1 mg by im injection Rectal: One 5 mg suppository every 4-6 hours as needed. Not for use in children under 12 years. PAPAVERETUM By sc, im or iv injection, 7.7-15.4 mg repeated every 4 hours if necessary; Elderly initially 7.7 mg; Child up to 1 month 115.5 micrograms/kg, 1-12 months 115.5-154 micrograms/kg. 1-12 years 154-231 micrograms/kg. In general the iv dose should be quarter to half the corresponding sc or im dose. Papaveretum and hyoscine injection - premedication, by sc or im injection, 0.5-1 ml. PENTAZOCINE Pain - oral 50mg every 3-4 hours (range 25-100 mg); Child 6-12 years 25 mg. By sc, im or iv injection moderate pain 30mg, severe pain 45-60 mg every 3-4 hours when necessary; Child over 1 year, by sc or im injection, up to 1 mg/kg, by iv injection up to 500 microgram/kg. Suppositories 50 mg up to 4 times daily. Child not recommended. PETHIDINE Pain - oral 50-150 mg every 4 hours; Child 0.5-2 mg/kg. Sc or im injection, 25-100 mg repeated after 4 hours; Child im injection 0.5-2 mg/kg. Slow iv injection, 25-50 mg, repeated after 4 hours Obstetric analgesia - sc or im injection 50-100 mg, repeated 1-3 hours later if necessary; max 400 mg in 24 hours. Premedication - by im injection, 25-100 mg 1 hour before operation; Child 0.5-2 mg/kg. Adjunct to nitrous oxide-oxygen, by slow iv injection, 10-25 mg repeated as required. Pamergan P100 - by im injection, for obstetric analgesia, 1-2 ml every 4 hours if necessary; severe pain, 1-2 ml every 4-6 hours if necessary. Premedication - 2 ml by im injection 1-1´ hours before operation; Child, by im injection, 8-12 years 0.75 ml, 13-16 years 1 ml. PHENAZOCINE Severe pain - oral or sublingual, 5 mg every 4-6 hrs when necessary; single doses may be increased to 20 mg; Child not recommended. PHENOPERIDINE Analgesia during operation, enhancement of anaesthetics, by iv injection, with spontaneous respiration, up to 1 mg, then 500 micrograms every 40-60 minutes as required; child 30-50 micrograms/kg. With assisted ventilation, 2-5 mg, then 1 mg as required; child 100- 150 micrograms/kg. PHOLCODINE Dry or painful cough Pholcodine linctus - 5-10 ml 3-4 times daily; child 5-12 years 2.5-5 ml. Pholcodine linctus, strong - 4 ml 3-4 times daily. Paediatric linctus - child 1-5 years 5 ml 3 times daily; 6-12 years 5-10 ml. TRAMADOL Moderate to severe pain - oral 50-100 mg not more often than every 4 hours; total of more than 400 mg daily not usually required; Child not recommended. By im or iv injection (over 2-3 minutes), or iv infusion, 50-100 mg every 4-6 hrs. Postoperative pain, 100 mg initially then 50 mg every 10-20 minutes if necessary during first hour to total max 250 mg (including initial dose) in first hour, then 50-100 mg every 4-6 hours; max 600 mg daily. Child not recommended. Modified release - 100 mg twice daily increased if necessary to 150-200 mg twice daily; total of more than 400 mg daily not usually required; child not recommended. NALOXONE 2 mg (adult) or 0.01 mg/kg body weight for children if coma or respiratory depression are present. Repeat the dose if there is no response within two minutes. Child, 0.01 mg/kg body weight for children if coma or respiratory depression are present. Repeat the dose if there is no response within two minutes. NALTREXONE To prevent relapse in detoxified formerly opioid dependent patients: 25 mg initially then 50 mg daily; the total weekly dose may be divided and given on 3 days of the week for improved compliance. Child not recommended. Contraindications Known opiate sensitivity. Avoid in acute respiratory depression, acute alcoholism and where risk of paralytic ileus. Not indicated for acute abdomen. Avoid in raised intracranial pressure or head injury (in addition to interfering with respiration, affect pupillary responses vital for neurological assessment). Avoid injection in phaeochromocytoma (risk of pressor response to histamine release). Abuses Dependence can occur with most of the opioid analgesics; it is not generally a problem when they are used legitimately. All opiates, in particular diamorphine (heroin), have potential for abuse because of their euphoriant effect. Dependence can develop rapidly with repeated administration. EPIDEMIOLOGY EPIDEMIOLOGY OF POISONING In 1991 226 deaths (190 male, 36 female) were attributed to opiates and related narcotics. This represents 11.4% of deaths from poisoning by drugs, medicaments and biological substances. 144 deaths (130 male, 14 female) were due to accidental poisoning, 32 (20 male, 12 female) to suicide and self-inflicted injury, 1 (female) to homicide and injury purposely inflicted by other persons, and 49 to injury undetermined whether accidentally or purposely inflicted (HMSO Mortality Statistics). Codeine is a constituent of many over-the-counter analgesics commonly taken in overdosage, but its effects are usually (but not always) overshadowed by those of salicylate or paracetamol. Self-poisonings with combined preparations of dextropopoxyphene and paracetamol are now much less common than previously, although still pose potentially serious problems. Poisoning with morphine, heroin and methadone is usually the result of accidental iv overdosage by drug addicts due to the unpredictable potency of 'street' drugs. There are therefore likely to be marked differences in the incidence of this type of opioid poisoning, with a much larger problem expected in selected quarters of large cities than in rural areas. Dextromoramide and dipipanone are now rarely encountered (Proudfoot 1993). ADVERSE EFFECTS AND INTERACTIONS ADVERSE EFFECTS Opioid analgesics share many side-effects, although qualitative and quantitative differences exist. The most common effects include nausea and vomiting (particularly in the initial stages), constipation, drowsiness and confusion. Larger doses produce respiratory depression and hypotension, with circulatory failure and deepening coma. Other adverse effects include difficulty with micturition, ureteric or biliary spasm, dry mouth, sweating, headache, facial flushing, vertigo, bradycardia, tachycardia, palpitations, postural hypotension, hypothermia, hallucinations, dysphoria, mood changes, dependence, miosis, decreased libido or potency, rashes, urticaria, and pruritis. Nystagmus was reported in a woman who received tetracaine and preservative-free morphine intrathecally. Naloxone reversal was successful (Ueyama et al, 1992). Paradoxical pain responses have been reported with high-dose therapeutic use of nalbuphine and buprenorphine with naloxone. A case of seizures following pethidine administration has been reported in a child (Kyff & Rice, 1990). A case of jerking movements progressing to seizures and unconsciousness was reported in a 60-year-old man given 25 mcg/kg alfentanil over 30 seconds (Strong & Matson, 1989). Myoclonic activity has been reported in two patients on high-dose spinal opioid therapy for pain (Parkinson et al, 1990). High-dose pethidine has been reported to cause muscle twitching (Morisy & Platt, 1986). A trauma victim given high doses of nalbuphine (up to 300 mg/day) experienced nightmares and extreme pain. INTERACTIONS Alcohol - enhanced sedative and hypotensive effect Anti-Arrhythmics - delayed absorption of mexiletine Antibacterials rifampicin accelerates metabolism of methadone (reduced effect); erythromycin increases plasma concentration of alfentanil ciprofloxacin - manufacturer advises avoid premedication with opioid analgesics (reduced plasma ciprofloxacin concentration) Anticoagulants - dextropopoxyphene enhances effects of warfarin and nicoumalone Antidepressants - CNS excitation or depression (hypertension or hypotension) with MAOIs (including moclobemide) and pethidine, and possibly other opioids Antiepileptics - carbamazepine - effect enhanced by dextropopoxyphene carbamazepine - decreases effect of tramadol Antipsychotics - enhanced sedative and hypotensive effect Antivirals - plasma concentration of zidovudine possibly increased by methadone Anxiolytics & Hypnotics - enhanced sedative effect Cisapride - possible antagonism of gastro-intestinal effect Dopaminergics - hyperpyrexia and CNS toxicity with selegilene Metoclopramide & Domperidone - antagonism of gastro-intestinal effects Ulcer-Healing Drugs - cimetidine inhibits metabolism of opioid analgesics notably pethidine (increased plasma concentration) MECHANISM OF ACTION / TOXICITY Opioid analgesics possess some of the properties of naturally occurring opioid peptides, including encephalins, endorphins and dynorphins. Pharmacologically the opioid analgesics are broadly similar, qualitative and quantitative differences may be dependent on their interaction with opioid receptors. There are several types of opioid receptor, distributed in distinct patterns through the central and peripheral nervous systems. The three main types in the CNS have been designated µ (mu), (kappa) and (delta). µ - analgesia (mainly supraspinal sites), respiratory depression, miosis, reduced gastro-intestinal motility and euphoria; µ1 (supraspinal analgesia) and µ2 (respiratory depression and gastro-intestinal activity) subtypes have been postulated. kappa - analgesia (mainly in the spinal cord), less intense miosis and respiratory depression, dysphoria and psychomimetic effects delta - probably analgesia, selective for encephalins Other receptors include (sigma) and (epsilon). The psychomimetic effects of agonist-antagonists such as pentazocine that are poorly antagonised by naloxone have been thought to be mediated by sigma receptors. Opioid analgesics act at one or more of these receptors as full agonists, partial agonists, or antagonists. Opioid analgesics have differing affinities for particular receptors and different degrees of activation once bound. A weak or partial agonist, is a partial agonist at one receptor site and has some antagonist activity at other receptors. Opioid antagonists are those drugs that bind but do not activate opioid receptor sites. Naloxone, an opioid receptor antagonist, acts at µ, kappa and delta receptor sites. FEATURES OF POISONING Acute Effects Ingestion Summary Opioid overdosage may result in central nervous system and respiratory depression with hypoxia, hypotension, shock, gastric hypomotility with ileus, and noncardiogenic pulmonary oedema. Opioid overdose may result in central nervous system depression. Decreased mental status is one of the most prominent symptoms in a narcotic overdose, which may progress to coma. Lethargy and coma associated with pinpoint pupils occur frequently. Pupils may be dilated in the presence of severe acidosis, hypoxia, or respiratory depression. Prolonged coma may result due to delayed gastric emptying. Seizures, myoclonic reactions, and spongiform encephalopathy have been reported in abusers of opioids. Respiratory depression and apnea are characteristic effects of opioid overdose and when severe may result in severe hypoxia, leading to hypotension and shock, pulmonary edema, and respiratory arrest (Wilkes et al, 1981; Jaffe & Martin, 1990). Delayed onset respiratory depression has been described 3, 6, 9, 14 and 24 hours following oral methadone ingestions (Wilen et al, 1975; Sey et al, 1971; Geller et al, 1994). Prolonged toxicity of 24 to 48 hours duration including respiratory depression may occur in individuals overdosing with methadone (Sey et al, 1971; Romac et al, 1986; Gayle et al, 1991). Respiratory depression that was NOT reversible by naloxone 10 mg was reported in a 61-year-old woman who ingested 50 meptazinol 200 mg tablets (Davison et al 1987). Hypotension, cardiac arrhythmias, pulmonary hypertension and cyanosis have been reported following overdose. Hypotension and shock may occur, especially in the presence of prolonged and severe hypoxia (Miller et al, 1980; Whipple et al, 1994; Lawrenson et al, 1993). Atrial fibrillation has been reported following abuse of crude heroin in an adult male patient (Lawrenson et al, 1993). Pentazocine overdose has been associated with ventricular dysrhythmias (Stahl & Kasser, 1983). Bradycardia may develop in patients with severe respiratory depression (Sey et al, 1971). Increased pulmonary artery pressure, pulmonary wedge pressure, LVEDP, arterial pressure, and pulmonary vascular resistance may be noted following overdosage of butorphanol. Hypothermia has been reported following overdoses of opiates. Hypomotility with ileus may occur following overdose. Acute tubular necrosis secondary to rhabdomyolysis and myoglobinuria, glomerulonephritis, glomerulosclerosis, renal amyloidosis and renal failure have been reported in heroin abusers. Rhabdomyolysis has been reported following heroin abuse or seizures associated with opioid overdose (Blain et al 1985). Hypoglycaemia has been reported following a heroin overdose. ACTH inhibition may occur with therapeutic and toxic opioid doses. Haemolysis has occurred in some patients following administration of high doses of fentanyl. Seborrhoea may be seen following MPTP (a derivative of pethidine) overdose. Inhalation Inhalation of opioids may result from drug abuse by persons crushing and 'snorting' tablets. Clinical effects and treatment are based on the oral route of exposure. Airway obstruction and bronchospasm have been associated casually with inhalation of heroin heated over metal foil. Eosinophils have been detected in the peripheral blood and/or respiratory secretions in these patients. More investigation is needed to determine the factors and the mechanisms involved. Hughes & Calverley (1988) report three cases of severe acute asthma following inhalation of heroin vapor. Fatal respiratory arrest occurred in two of these patients. Delayed onset respiratory depression has been described 4 hours following intranasal heroin use (Steinberg & Karlinger, 1968). Dermal - NIF Ocular - NIF Other Routes Bronchospasm and wheezing have been reported in both intravenous and inhalational abusers of heroin. Respiratory arrest occurred in 3 patients after epidural infusion of fentanyl and bupivicaine. Each patient responded dramatically to naloxone (Weightman, 1991). If pulmonary oedema occurs it is generally abrupt in onset (immediate- 2 hours) following intravenous heroin overdose (Duberstein & Kaufman, 1971). An adult male who injected heroin once into his right brachial plexus area presented in a coma with acute pulmonary edema, flaccid paralysis of the ipsilateral arm and leg, and severe edema of the arm. Severe brachial plexitis was present, which the authors speculated was a hypersensitivity response (Stamboulis et al, 1988). Fever may occur several hours after injection of aqueous mixtures of pentazocine and tripelennamine tablets. Chronic Effects Ingestion Respiratory depression leading to respiratory arrest, pulmonary oedema, hypoxia, bronchospasm, acute asthma, bullous pulmonary damage and pneumonitis have occurred with therapeutic use and abuse of opioids. Coma, seizures, myoclonic reactions and spongiform encephalopathy have been reported in abusers of opioids. Grand mal seizures have been reported with doses of fentanyl. Seizures may occur with chronic use or abuse of pethidine and are often proceeded by myoclonus, are of limited duration, respond to conventional treatment, and resolve following a discontinuation of pethidine. Other signs of nervous system stimulation may continue for 7 days. 48 of 67 patients demonstrated agitation, tremors, myoclonus, or seizures following chronic pain therapy with pethidine. A Parkinson-like syndrome has been seen in abusers of pethidine analogues. PAIN High doses of opioids or combination opioid agonists/antagonists have been reported to cause a paradoxical pain reaction which resolves upon cessation of the drug. Severe respiratory depression and pain were reported after administration of a high dose of buprenorphine. These signs were alleviated after naloxone administration. PERIPHERAL NEUROPATHY HEROIN: De Gans et al (1985) report 7 patients who developed rhabdomyolysis and neuropathy of a peripheral nerve or nerve plexus after heroin abuse without evidence of muscle or nerve compression. Hypomotility with ileus may occur with chronic abuse, or in patients on methadone maintenance. Constipation is common. Tolerance does not develop. Naltrexone may cause dose-related increases in liver enzymes when used chronically. Morphine has been found to stimulate prolactin release. Opioids such as morphine are implicated in causing hypoglycaemia. Morphine and some other opioids have a histamine releasing effect which may be responsible for urticaria and pruritis. Urticarial rash has been reported during therapeutic use of codeine. Inhalation SPONGIFORM LEUCOENCEPHALOPATHY Spongiform leucoencephalopathy was reported in two patients who were regular heroin smokers. Both had neurological signs (cerebellar ataxia, bilateral pyramidal signs, dysarthria); CT scan and autopsy showed extensive white-matter spongiosis and vacuolization. "Chinesing," or inhaling preheated heroin, has been associated with severe neurological illness and postmortem findings of spongiform encephalopathy. Dermal - NIF Ocular - NIF Other routes iv injection Pain and irritation may occur on injection as morphine and some other opioids have a histamine releasing effect iv and intranasal PARKINSON'S SYNDROME A syndrome closely resembling moderate to severe idiopathic Parkinson's Disease has been described in intravenous and intranasal drug users following use of a derivative of pethidine, 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP). Symptoms may partially respond to levodopa and/or bromocriptine and usually slowly resolve over 18 months or longer. If recovery does not occur following an acute phase, a chronic and permanent parkinsonian syndrome is observed. Prolonged industrial exposure to MPTP has also resulted in Parkinsonism. AT RISK GROUPS Elderly Plasma half -lives of opiates are usually longer in older age groups due to reduced clearance. Adverse effects are likely to occur at lower doses than in younger adults Pregnancy Buprenorphine There are no studies on the use of buprenorphine in human pregnancy. Animal studies indicate that buprenorphine is not teratogenic in rats or rabbits (Heel et al 1979), but caused delayed parturition in the rat (Evans et al 1989). Codeine Despite the fact that codeine has been extensively used, there are very few data available on the effects of codeine in either animal or human pregnancy. Retrospective studies involving first trimester use of codeine have shown conflicting evidence of possible teratogenic effects. A wide range of anomalies have been associated with its use, including CVS defects, cleft lip and palate, musculoskeletal defects, dislocated hip and inguinal hernia (Saxen 1975a; Bracken & Holford 1981; Rothman et al 1979; Zeitler & Rothman 1985; Bracken 1986). Other studies involving over 1200 pregnancies found no significant increase in either major or minor malformations, or any pattern of defects (Saxen 1975b; Heinonen et al 1977; Jick et al 1981; Aselton et al 1985). Although the retrospective studies imply an association of codeine use with fetal malformations, the inherent bias and methods of data collection do not permit a causal relationship to be established. It would seem that occasional therapeutic use of codeine in pregnancy is not likely to cause fetal damage. Like other narcotic analgesics, codeine use near term or during delivery can produce respiratory depression in the neonate which can be alleviated by naloxone (Bonica 1967). Neonatal withdrawal symptoms eg. tremor, jitteriness, diarrhoea and poor feeding may be seen following either short term (prior to or during delivery) or long term use of codeine by the mother (van Leeuwen et al 1965; Mangurten & Benawra 1980). Codeine overdose in pregnancy Data from the UK TIS on a small number of pregnancies (16) in which the mother overdosed with codeine phosphate either alone or as a combined analgesic preparation does not suggest an increased fetal risk above the background rate in the absence of severe maternal toxicity. Dextropropoxyphene There are very few published data on the effects of dextropropoxyphene in human pregnancy. There are a small number of anecdotal case reports of malformations allegedly associated with its use, but with no recurrent pattern of malformations or syndrome of defects. From the data presented a causal relationship seems unlikely (Boelter, 1980; Golden et al 1982). The Boston Collaborative Perinatal Project identified 2914 women who had taken propoxyphene at sometime during their pregnancy, 686 were first trimester exposures. There was no increase in either major or minor malformations and no syndrome of defects was detected (Heinonen et al 1977). Similarly, in another cohort of over 100 pregnancies, all first trimester exposures, no increase in fetal toxicity was reported (Jick et al 1981). Transient neonatal toxicity i.e. withdrawal symptoms have been reported in the infants of mothers who were on long term therapy with dextropropoxyphene (Tyson, 1974; Klein et al 1975; Quillian & Dunn, 1976 and Ente & Mehra 1978). Irritability, hyperactivity, tremors and high-pitched cries are the most common features observed. Overdoses Follow-up data from the NTIS on over 400 cases of paracetamol overdose (including 40 taking coproxamol) during pregnancy shows no increase in the incidence of either spontaneous abortions or malformations in the absence of severe maternal toxicity. There were over 130 first trimester exposures. Diamorphine (heroin) No convincing evidence for an increase in abnormalities has been presented in humans but the numbers of mother/child pairs are too small to exclude an increase in abnormalities. All investigations are hampered by numerous confounding factors. There is conformity in numerous reports of an increased frequency of growth retardation including reduced head circumference, and in perinatal mortality. Retardations in development of the babies is reported and in some studies may predominantly be due to inadequacies in postnatal care. In a high proportion of newborns from heroin using mothers, withdrawal symptoms are seen lasting a few days or weeks but may persist for several months, though only a low percentage of the infants require therapy. Methadone The data available relate to use of heroin and methadone in pregnancy, and provide no convincing evidence for an increased risk of malformations. However, the number of mother-child pairs is small. The most consistent findings are; IUGR, decreased head circumference, and increased perinatal mortality. It is not clear whether the retardation in postnatal development are directly related to drug exposure in utero or to deficiencies in postnatal care. A high proportion of the babies have neonatal withdrawal symptoms which may last from several days -months. In some pregnancies substitution of methadone for heroin seems to reduce pregnancy risks . However the withdrawal symptoms in the neonate are often more severe and persistent. Higher risk of SIDS (Sudden Infant Death Syndrome). If exposure is to continue throughout pregnancy, it would be important to ensure adequate maternal nutrition and monitor fetal growth. Access to good paediatric care would be essential. Morphine No evidence linking the therapeutic use of morphine with abnormalities (Heinonen et al 1977). Case reports have associated use of morphine in the first trimester with malformations, but other drugs were also taken so it is difficult to establish a causal relationship. Neonatal respiratory depression may occur at birth if morphine is used during labour. Neonatal withdrawal effects may be seen in the infants of addicted mothers 12 to 72 hours after birth. Infants may be dehydrated, irritable, and experience tremors and cry continually. Naloxone There is little data available on the use of naloxone during human pregnancy. Animal studies do not indicate any teratogenic effects. Few adverse neonatal effects have been seen when naloxone has been used to antagonise respiratory depression following maternal analgesic use. There have been case reports of naloxone induced fetal asphyxia (Goodlin 1981) and fits in the neonate of an opiate addict (Gibbs et al 1989). Pentazocine There are few data available on the effects of pentazocine in human pregnancy. Animal studies in rats and rabbits showed no evidence of adverse effects on fertility, length of gestation, litter size or fetal development. Pentazocine crosses the human placenta, and has been associated with enhanced uterine activity but no adverse fetal effects (Filler & Filler 1966). Neonatal withdrawal effects may occur if pentazocine is used near term. Tramadol There are no published data on the outcome of human pregnancy after tramadol exposure in the first trimester. Tramadol has been used during labour with no significant adverse effects on the fetus/neonate. Animal studies have not demonstrated any increase in fetal malformation. Searle have outcome data from 9 pregnancies: 3 premature deliveries - no malformations (2x 1st trimester and 1x1-3 trimester exposures) 1 neonatal opiate withdrawal - no malformations (1-3 trimester exposure) 1 neonatal convulsions - no malformations (exposed at 38/40) 2 Caesarean deliveries - no malformations (1 for fetal distress - exposed just prior to delivery, 1 for uterine rupture - exposed at 5/40) 1 maternal and fetal death (malaria infection) - 3rd trimester exposure 1 spontaneous abortion at 7/40, exposed at 4-5/40 1 ETOP (spina bifida) - exposed at 15/40 - therefore not causally related to tramadol Children Plasma half-lives of opiates are usually longer in children due to reduced clearance. Others Addicts Addicts develop tolerance to high doses which would be fatal to a new user. Addicts experience withdrawal symptoms on discontinuation of drug. Renal impairment Patients with renal impairment have increased systemic effects. Hepatic dysfunction Some patients with hepatic dysfunction are especially sensitive to opioids and experience prolonged sedation and respiratory depression, whereas many patients with liver impairment are able to tolerate opioids normally. MANAGEMENT Decontamination If patient is unconscious or has respiratory depression, attend to this first - see supportive care (airway and naloxone). Opiates delay gastric emptying and may be slow release (MST). Slow release preparations have a slower onset of action and increased duration of action than immediate release preparations. In overdose, onset of symptoms may be delayed, but last longer, thus continued observation and supportive care will be indicated. Gastric lavage carries the risk of gut perforation and aspiration. Endotracheal intubation is mandatory in unconscious patients or those with poor gag reflexes. Activated charcoal may be a safer option, however, lavage may be justified if performed soon after ingestion for very large overdoses, especially in the presence of alcohol as activated charcoal is less effective in these circumstances. Induction of emesis is not recommended because of the potential for CNS depression and seizures. For the asymptomatic body packer whole bowel irrigation may be a relatively safe and effective means of rapid decontamination (see case data). Prevention Of Absorption Activated charcoal is effective for reducing the absorption of opiates for up to 4 hours post ingestion (Proudfoot suggests up to 6 hours) as opiates delay gastric emptying. The dose should be at least 10 times the quantity of drug taken. Doses of 50-100 g (adults) or 25-50 g (children) should be aimed for. Lactulose (20 ml) should be given to prevent constipation. Patients who vomit, or who have reduced levels of consciousness can be treated via a nasogastric tube protecting the airway if necessary. Supportive care Support respiratory and cardiovascular function. If the patient is unconscious or has respiratory depression: Ensure clear airway ADULTS: give naloxone 800 mcg IV to start, then 400 mcg every 2 minutes until the patient improves (respiratory rate, consciousness, pupil size) or until 3.2 mg have been given. CHILDREN: 0.01 mg/kg body weight if coma or respiratory depression are present. Repeat the dose if there is no response within two minutes. A larger dose of 0.1 mg/kg may be used if no improvement is seen, or response is sub-optimal. NEONATES: Initial doses of 10 to 30 mcg/kg IV are recommended. Failure of a definite opioid overdose to respond to naloxone suggests that another CNS depressant drug or brain damage is present. Observe the patient carefully for recurrence of CNS and respiratory depression. The plasma half-life of naloxone is shorter than that of most opioid analgesics. Relapse may occur after 20 minutes. Repeated doses of naloxone may be required. Intravenous infusions of naloxone have been recommended in situations where repeated doses have been necessary. Set up an infusion (5 x 400 mcg ampoules naloxone = 2 mg in 500 ml 5% dextrose) at a rate equal to 2/3 of the dose required to wake the patient per hour. Infusions are not substitutes for frequent review of the patients clinical state and administration of bolus doses of naloxone as required. Do not delay in establishing a clear airway, adequate ventilation and oxygenation if there is no response to naloxone. If pulmonary oedema is a complication maintain ventilation and oxygenation with close arterial blood gas monitoring. Assisted ventilation with positive expiratory pressure may be necessary. SEIZURES Administer diazepam IV bolus (DOSE: ADULT: 5 to 10 mg initially which may be repeated every 15 minutes PRN up to 30 mg. CHILD: 0.25 to 0.4 mg/kg/dose up to 10 mg/dose). If seizures cannot be controlled or recur, administer phenytoin or phenobarbitone. HYPOTENSION: Administer IV fluids and place in Trendelenburg position. If unresponsive to these measures, administer dopamine (2 to 5 mcg/kg/min) (first choice) or norepinephrine (0.1 to 0.2 mcg/kg/min) and titrate according to response. PARKINSON'S SYNDROME A syndrome closely resembling moderate to severe idiopathic Parkinson's Disease has been described in intravenous and intranasal drug users following use of a derivative of pethidine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Symptoms may partially respond to levodopa and/or bromocriptine and usually slowly resolve over 18 months or longer. Other supportive measures as indicated by the patient's progress. Monitoring Plasma opioid levels are not clinically useful. Treatment is based more on clinical presentation than on specific laboratory data. Monitor arterial blood gases, pulmonary function, and chest x-ray for patients with significant exposure. Patients with intravenous overdose requiring naloxone reversal should be monitored for 4 hours after the last dose of naloxone to observe for evidence of pulmonary edema. Patients with oral opioid overdose should be monitored for 6 hours and admitted if signs or symptoms develop. Patients with overdose of methadone or other long acting opioids require admission as clinical effects may be delayed. Antidotes NALOXONE A pure opioid antagonist, may be used for the complete or partial reversal of opioid depression, including mild to severe respiratory depression induced by natural and synthetic opioids, the agonist/antagonists nalbuphine and pentazocine, or dextropropoxyphene. It may also be used for the diagnosis of suspected acute opioid overdose. Adverse effects Abrupt reversal of narcotic depression may result in nausea, vomiting, sweating, tachycardia, increased blood pressure, tremulousness, seizures and cardiac arrest. Acute withdrawal effects may be precipitated in large opioid overdoses, or in patients physically opioid dependent. In postoperative patients, larger than necessary dosage of naloxone may result in significant reversal of analgesia and excitement. Hypotension, hypertension, ventricular tachycardia and fibrillation, and pulmonary oedema have been associated with postoperative use of naloxone. Hoffman et al (1991) recommend administering naloxone only to altered mental status patients with bradypnoea (respirations of 12 or less) in questionable opiate overdoses. DOSE Adults Opioid overdose: 0.8-2 mg by iv injection repeated at intervals of 2-3 minutes up to a maximum of 10 mg if respiratory function does not improve (question diagnosis). Can also be given by sc or im injection if no iv access. Post-operative use: 100-200 mcg iv is usually sufficient, a full 2 minutes should be allowed to elapse between each 100 mcg increment. The dose should be titrated for each patient to obtain optimum respiratory response while maintaining adequate analgesia. Children: Initial iv dose 10mcg/kg, a subsequent dose of 100 mcg/kg may be given according to response. Neonates: Infants born to mothers given analgesics in labour, initial iv, im or sc dose of 10 mcg/kg, repeated after 2-3 minutes according to response. Alternatively, a single dose of 200 mcg (approx. 60 mcg/kg) may be given im at birth. Observe the patient carefully for recurrence of CNS and respiratory depression. The plasma half-life of naloxone is shorter than that of most opioid analgesics, particularly dextropropoxyphene, dihydrocodeine and methadone. Relapse may occur after 20 minutes. Repeated doses of naloxone may be required. Intravenous infusions of naloxone have been recommended in situations where repeated doses have been necessary. Set up an infusion (5 x 400 mcg ampoules naloxone = 2 mg in 500 ml 5% dextrose) at a rate of 2/3 of the dose required to wake the patient per hour. Infusions are not substitutes for frequent review of the patients clinical state and administration of bolus doses of naloxone as required. Alternative routes Subcutaneous or intramuscular routes may be effective if iv route is not feasible (onset of action slower). Naloxone can also be given intralingually or intrathecally in the absence of intravenous access. CASE DATA CODEINE A 3-month-old preterm infant received codeine 6.6 mg/kg within 24 hours, well above the recommended dose of 1 to 2 mg/kg. The infant developed apnea and presented at the hospital with pinpoint pupils and was semi-comatose. Effects were reversed with IV naloxone (Wilkes et al, 1981). A 30 year old woman was admitted after having ingested 100 compound aspirin / codeine tablets (30 g aspirin and 800 mg codeine) and an unknown amount of diazepam. She was drowsy but responded to verbal commands, had pinpoint pupils, and was sweating and hyperventilating with a pulse rate of 115/min and blood pressure of 120/80 mm Hg. Arterial blood gas analysis showed a mixed respiratory alkalosis and metabolic acidosis pH 7.4, carbon dioxide tension 3.1 kPa, oxygen tension 13.6 kPa and bicarbonate 15 mmol/l. Immediately after administration of naloxone (0.8 mg iv) the pupils dilated and she became fully conscious. Plasma salicylate and codeine concentrations were 1006 mg/l and 650 mcg/l respectively. Plasma urea, sodium and potassium concentrations were normal. Diazepam and nordiazepam concentrations were 0.38 mg/l and 0.84 mg/l respectively. Forced alkaline diuresis was performed; 21 hours post admission the plasma salicylate concentration measured 462 mg/l. On 3 occasions during forced alkaline diuresis her conscious level deteriorated such that she responded only to painful stimuli and pinpoint pupils. These effects were reversed by naloxone, with a further 4 mg being administered in total. The authors also report a second case (Leslie et al 1986). DEXTROPROPOXYPHENE Young & Lawson (1980) reviewed 82 patients admitted with acute Distalgesic(R) poisoning. On admission 20 patients had grade 4 and 2 had grade 3 coma; 12 had respiratory arrest, 4 severe convulsions, 3 aspiration pneumonia, 1 cardiac arrest and 3 patients died. All of the complication were considered directly attributable to dextropropoxyphene and were treated with naloxone and assisted ventilation where appropriate. 23 patients had one or more of these complications. A 14 day old infant weighing 4.43 kg was admitted to hospital after his 2 yr old brother was discovered feeding him Distalgesic(R) 2 hours previously. One hour after ingestion the infant became pale, drowsy and unresponsive with shallow respirations. On arrival at hospital he was pale, mottled and limp. The pupils were markedly constricted and he was practically apnoeic with only occasional shallow gasps. Naloxone 0.1 mg im resulted in complete recovery after only 20-30s. Four further episodes of apnoea occurred, responding to naloxone each time. The infant was discharged home after 4 days. FENTANYL A 36 year old male became intoxicated from fentanyl by heating and inhaling the contents from a fentanyl patch. He collapsed after 1 inhalation with a respiratory rate of 6/min, heart rate of 120 bpm and an unobtainable blood pressure. He responded to naloxone injection 2 mg iv and was discharged a few hours later with stable vital signs and mental status (Marquardt and Tharratt, 1994). The patient died following a subsequent inhalation session. HEROIN A 31-year-old male ingested 28 heroin-containing packets in an attempt to clear US Customs. The patient received a total of 31 litres of whole bowel irrigation, with polyethylene glycol electrolyte lavage solution, over the course of 52 hours, which resulted in the successful recovery of all packets. The procedure was well tolerated except for one episode of hypoglycemia. Lab data remained within normal limits and the patient denied abdominal cramping throughout the procedure (Betzelos & Mueller, 1991). A review article of the literature on opioid body-packers is available (Stewart et al, 1990). Utecht et al (1992) present a series of 14 patients, nine of whom swallowed heroin-containing packets and five of whom inserted them rectally. Thirteen had evidence of packets on KUB. Bisacodyl suppositories were used to evacuate packets from the rectum. No patient received ipecac or gastric lavage. MEPTAZINOL Respiratory depression that was NOT reversible by naloxone 10 mg was reported in a 61-year-old woman who ingested 50 meptazinol 200 mg tablets (Davison et al, 1987). RHABDOMYOLYSIS Blain et al (1985) report 3 cases of opiate overdose were the patients developed acute muscle damage with elevated serum aspartate aminotransferase and creatine kinase activities, increased serum myoglobin concentrations, raised plasma creatinine concentrations, hypocalcaemia and hyperphosphataemia. The abnormalities gradually resolved over 7-10 days, but recovery was complicated due to the development of acute renal failure (requiring haemodialysis) in one patient. Plasma drug concentrations, shortly after admission, in the patients taking dihydrocodeine and morphine were grossly elevated (184 and 60 mcg/l respectively). Clinical evidence of myopathy was minimal in all three patients and muscle biopsy of one patient was normal at 7 days. Author Kathryn Pughe, BSc (Hons) MRPharmS National Poisons Information Service (Newcastle Centre) Regional Drug & Therapeutics Centre Wolfson Building Claremont Place Newcastle upon Tyne NE1 4LP UK This monograph was produced by the staff of the Newcastle Centre of the National Poisons Information Service in the United Kingdom. The work was commissioned and funded by the UK Departments of Health, and was designed as a source of detailed information for use by poisons information centres. Peer review was undertaken by the Directors of the UK National Poisons Information Service. Last updated June 1997 REFERENCES JOURNALS 1. Aselton P, Jick H, Milunsky A, Hunter JR, Stergachis A. First trimester drug use and congenital disorders. Obstet Gynecol 1985; 65: 451-455. 2. Beattie JO, Chen CP, MacDonald TH. Neonatal Distalgesic poisoning. Lancet 1981; : 49. 3. BetzelosS, Mueller P. Whole bowel irrigation in a heroin body- packer (Abstract). Vet Hum Toxicol 1991; 33: 353. 4. 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See Also: Opioids (Group PIM G023)